The goals of the proposed research project are: 1) to prepare and train the candidate for a career in academic gastroenterology by providing the necessary environment, education, and research support, and 2) to gain insight into the epidemiology of hepatocellular carcinoma in the United States. The candidate is a clinically trained gastroenterologist with additional training in basic epidemiology and biostatistics. As part of this proposal, she will be provided with more advanced training in both general and applied epidemiology and biostatistics. The candidate will be supported and mentored by Dr. John Potter. Her progress will be monitored by the sponsor and the Division of Gastroenterology. The Department of Medicine and Division of Gastroenterology will provide full commitment and support toward the development of the candidate's independent research career. The focus of the scientific portion of this proposal is on hepatocellular carcinoma, a common tumor worldwide the incidence of which is also rising in the United States. Much of this increase can be attributed to the current epidemic of hepatitis C. The epidemiology of hepatocellular carcinoma has not been extensively studied in this country, and few studies have recruited population-based cases and controls. Well-recognized environmental risk factors for hepatocellular carcinoma include chronic viral hepatitis, other chronic liver diseases, and exposure to aflatoxins. However, risk factors that predispose patients with chronic liver disease to hepatocellular carcinoma are not well defined. It is likely that genetic risk factors for hepatocellular carcinoma exist, since familial and ethnic clustering of the tumor are well documented, iron is a recognized co-factor for the development of malignancy in other sites. Hemochromatosis is an inherited disorder in which excess iron accumulates in the liver, heart, pancreas, and other organs. A gene for hemochromatosis, HFE, has recently been identified. Patients with hemochromatosis are at up to 200-fold increased risk of developing hepatocellular carcinoma. We hypothesize that HFE mutations are risk factors for HCC in patients either with or without underlying liver disease. Thus, the specific aims of tills proposal are: 1) to determine whether mutations in the HFE gene are a risk factor for hepatocellular carcinoma; and 2) to recruit a cohort of patients with chronic hepatitis C for prospective studies of the epidemiology of hepatocellular carcinoma.